The study population consisted of two groups of Japanese patients. In the first group were Japanese patients who had completed an initial 6 week, double-blind, placebo-controlled, evaluation (Kato et al. 2020) of lurasidone in the treatment of bipolar depression and enrolled in a subsequent 52 week open-label extension phase. This group is labeled the “depressed episode” sample here. In the second group were Japanese patients with bipolar I disorder whose current or most recent episode was a mania (ie, meeting criteria for DSM-IV-TR specifier 296.4x), hypomania (DSM-IV-TR specifier 296.40), or mixed (DSM-IV specifier 296.6×) episode. This group is labelled the “non-depressed episode” sample here. This latter group of patients enrolled directly into a 52 week long-term lurasidone study (without a preliminary 6 week double-blind phase).

Patients from both routes of enrollment were male and female outpatients 18–74 years of age. For the non-depressed group, patients who were willing to initiate treatment with lithium or VPA adjunctively were enrolled. The 6 week, double-blind study enrolled patients with a DSM-IV-TR diagnosis of bipolar I disorder (with or without rapid cycling) who were currently experiencing a major depressive episode of at least 4 weeks but less than 12 months in duration. Patients who had completed the 6 week double-blind trial and were considered to be without safety concerns were eligible for the subsequent long-term study. For the second route of enrolment, patients with a DSM-IV-TR diagnosis of bipolar I disorder (with or without rapid cycling) were eligible if their current or most recent episode was a mania, hypomania, or mixed episode. For both the group of patients who had participated in the prior 6 week trial and the newly recruited patients who did not have an initial 6 week double-blind phase, the key exclusion criteria were: (1) presence of another Axis I or Axis II disorder other than bipolar disorder that was the focus of treatment received in the 3 months prior to screening, (2) a score of ≥ 4 on MADRS item 10 (suicidal thoughts) (at week 6 for those who participated in the prior 6 week double-blind study; at screening or baseline for those newly recruited patients who did not have an initial 6 week double-blind phase), (3) had a history of nonresponse to an adequate (6 week) trial of three or more antidepressants, antipsychotics, lithium, or VPA during the current episode, and (4) were judged to be an imminent risk of suicide, injury to self, others, or property. Diagnosis was determined using the Mini-International Neuropsychiatric Interview (Sheehan et al. 1998).

The 6 week double-blind study, the subsequent long-term extension phase, and the study recruiting patients with a manic, hypomanic, or mixed episode directly into a 52 week long-term treatment period, were each reviewed and approved by institutional review boards at each investigational site. The studies were conducted in accordance with the International Conference on Harmonization Good Clinical Practices guidelines and with the ethical principles of the Declaration of Helsinki. All patients reviewed and signed an informed consent document explaining study procedures and potential risks prior to enrollment in the 52 week long-term treatment study.

This study was a 52 week open-label flexible-dose study of lurasidone with or without a lithium or VPA. The initial 6 week double-blind study recruited patients at 102 centers in 8 countries. Only those recruited at 76 centers in Japan were included in the current report. The study, including the double-blind treatment phase and 52 week open-label phase, was conducted between January 22, 2014 and February 17, 2018.

All patients who had participated in the prior 6 week double-blind study started the 52 week extension study at a lurasidone dose of 60 mg/day for 1 week to maintain the blind of the 6 week trial until the 6 week dataset was ready for analysis. For the newly recruited patients who did not participate in an initial 6 week double-blind study, the starting dose was 20 mg/day followed by a gradual dose escalation. Lurasidone was taken once daily, within 30 min after the evening meal and administered at a flexible dose (20–120 mg/day) for 52 weeks. The dose of lurasidone could be increased or decreased by 20 mg/day at the scheduled visits, and could be increased by 20 mg/day at unscheduled visits at least 7 days after the prior visit. Dose increases were only permitted once a week between scheduled visits. When any safety concerns were raised, the dose could be reduced by 20 mg/day at unscheduled visits without waiting for 7 days.

Concomitant use of either lithium or VPA was not mandatory for the completers of the prior 6 week double-blind study because these drugs were prohibited in that prior study. The decision to add a mood stabilizer for patients who had completed the prior 6 week study was a clinical decision by the investigator at each site based on patient symptoms. For patients who had not participated in the prior study (non-depressed episode sample), concomitant use of either lithium or VPA was mandatory in order to evaluate the long-term efficacy and safety of lurasidone adjunctive to a mood stabilizer. The dose of lithium and VPA could be modified based on the patient’s condition and serum concentrations that were obtained at each study visit. If necessary, the investigator could use either lithium or VPA at a lower or higher dose than approved with prior consultation with the medical monitor. If any safety concerns were raised, treatment with either lithium or VPA was to be terminated.

Prohibited during the 6 week double-blind and the 52 week long-term study were CYP3A4 inhibitors and inducers, Chinese herbal medications, Ginkgo Biloba extract, Kava Kava, depot antipsychotics, MAO inhibitors, clozapine, fluoxetine, olanzapine/fluoxetine combination, electroconvulsive therapy, and St. John’s wort. Lorazepam (≤ 2 mg/day) was permitted as needed (but prohibited within 8 h of an assessment) for the treatment of anxiety, agitation, irritation, and other psychiatric symptoms/signs. Hypnotics were permitted for insomnia. For patients untreated with antiparkinson agents at screening, such medications were prohibited from screening until the initiation of the study treatment. For patients who had completed the prior 6 week study and who had received antiparkinson drugs or other drugs for extrapyramidal symptoms at the initiation of the study treatment, the drugs were to be continued without any dosage modification. For patients who had not participated in the prior study and who had received antiparkinson drugs or other drugs for the treatment of extrapyramidal symptoms at screening, drugs for extrapyramidal symptoms were titrated down and terminated before initiating study treatment. If any extrapyramidal symptoms developed or worsened after the initiation of the study treatment, permitted antiparkinson medications included biperiden (≤ 16 mg), trihexyphenidyl (≤ 10 mg), benztropine (≤ 6 mg), and diphenhydramine (≤ 300 mg). For akathisia, propranolol (≤ 120 mg/day), amantadine (≤ 300 mg/day), or one of the allowable antiparkinson medications was permitted.

Safety and tolerability were assessed throughout the study by the incidence and severity of treatment-emergent adverse events (TEAEs), laboratory measures of prolactin, glucose metabolism, and lipid metabolism, vital signs, body weight, and QTc interval determined from electrocardiography (ECG) measurements. Treatment-emergent mania was defined in depressed group as a YMRS total score of ≥ 16 at any 2 consecutive post-long-term-baseline visits or at the final assessment, or an adverse event of mania or hypomania. The influence of treatment on extrapyramidal symptoms was evaluated by the occurrence of extrapyramidal AEs, the proportion of patients using concomitant antiparkinson drugs, changes on the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS; Inada et al. 2003) total score (excluding overall severity). The proportion of patients with any instance of suicide attempt or suicidal ideation was measured by the Columbia-Suicide Severity Rating Scale (C-SSRS; Chappell et al. 2012). The DIEPSS, C-SSRS, body weight, and vital signs were obtained at long-term study baseline and post-long-term baseline weeks 1, 2, 4, and every 4 weeks up to week 52. ECGs and laboratory tests were obtained at long-term baseline and week 4 and every 8 weeks up to week 52.

Symptom and functioning measures included the Montgomery-Åsberg Depression Rating Scale (MADRS; Montgomery and Åsberg 1979) total score (range: 0–60), Young Mania Rating Scale (YMRS; Young et al. 1978) (range: 0–60), the Clinical Global Impression: Bipolar Version -Severity of Illness (CGI-BP-S; Spearing et al. 1997) depression score (range: 1–7), the Sheehan Disability Scale (SDS; Sheehan 1983) total score (range: 0–30), and the Hamilton Anxiety Rating Scale (HAM-A; Hamilton 1959) (range: 0–56). Trained raters conducted the assessments at each visit. The MADRS, YMRS, and CGI-BP-S were obtained at long-term baseline and post-long-term baseline weeks 1, 2, 4, and every 4 weeks up to week 52. The SDS and HAM-A were obtained at long-term baseline and week 4 and every 8 weeks up to week 52.

An additional endpoint was the proportion of patients who experienced a recurrence or relapse of a mood event from clinical stability. Recurrence/relapse of a mood event was defined as the occurrence of any of the following: (1) fulfilled DSM-IV-TR criteria for major depressive, manic, hypomanic, or mixed episode; (2) required treatment intervention for depressive, manic, hypomanic, or mixed symptoms with antipsychotics (other than the study drug), antidepressants, mood stabilizers (other than lithium and VPA), anxiolytics, or benzodiazepines (treatment with lorazepam, temazepam, zolpidem, zolpidem CR, eszopiclone, or zaleplon within the permitted dose range was not applied to this criterion), (3) psychiatric hospitalization for any bipolar mood episode, (4) YMRS or MADRS total score ≥ 18 or at least one of the CGI-BP-S (overall, depression, mania) scores ≥ 4 at 2 consecutive visits no more than 10 days apart, or (5) discontinuation from the study because of a mood event (as determined by the investigator). Clinical stability (sustained response) of bipolar disorder was defined as total scores of ≤ 12 on the MADRS and YMRS over at least 12 weeks, with the allowance of 2 exceptions (the YMRS and/or MADRS total scores up to 13 or 14, respectively) as long as these exceptions did not occur during the last 4 weeks before achieving clinical stability. Time to recurrence/relapse following the achievement of clinical stability was also analyzed, as was time until all-cause discontinuation.

All analyses were performed on the population of patients who took at least one dose of long-term study drug. Week 6 of the double-blind study was considered to be the baseline of the long-term study for patients who were enrolled in the prior study. Descriptive statistics were used to summarize safety and symptom/functioning data. Number and percent of patients with TEAEs over the course of the 52 weeks were summarized. Mean (SD) change from long-term baseline to week 52 was calculated for laboratory tests, vital signs, body weight, ECG parameters, and the DIEPSS. Symptom and functioning variables were examined in terms of mean changes from long-term baseline to endpoint (LOCF). For time to clinical stability and time to all cause discontinuation, median and its 95% confidence interval using the product-limit method were calculated. The numbers and percentages of subjects who experienced a recurrence/relapse and clinical stability were summarized. Analyses were conducted for all patients, and also separately for patients who received lurasidone and for those who received placebo in the prior 6 week double-blind study, as well as for the patients who had not participated in the prior study as a group and separately by type of current/recent episode.